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Pharmaceuticals and Medical
Devices Safety Information
No. 281
July 2011
Table of Contents
1. Revision of Package Inserts of
Subcutaneous Port and Catheter ............................................................. 5
2. Important Safety Information ...................................................................... 8
(1) Freeze-dried Live Attenuated Measles Vaccine; Freeze-dried Live Attenuated
Measles, Rubella Combined Vaccine.............................................................. 8
(2) Cisplatin (intra-arterial injection) ................................................................... 10
(3) Sitagliptin Phosphate Hydrate ...................................................................... 13
(4) Sorafenib Tosilate......................................................................................... 14
(5) Metformin Hydrochloride (products with “Dosage and Administration” of
maximum daily dosage of 2250mg) ............................................................. 16
3. Revision of Precautions (No. 227).......................................................... 20
Cortisone Acetate (and 9 others) ...................................................................... 20
4. List of Products Subject to
Early Post-marketing Phase Vigilance .................................................. 24
This Pharmaceuticals and Medical Devices Safety Information (PMDSI) is issued based on safety information
collected by the Ministry of Health, Labour and Welfare (MHLW). It is intended to facilitate safer use of
pharmaceuticals and medical devices by healthcare providers.
The PMDSI is available on the Pharmaceuticals and Medical Devices Agency (PMDA) website
(http://www.pmda.go.jp/english/index.html) and on the MHLW website (http://www.mhlw.go.jp/, only
available in Japanese language).
Published by
Pharmaceutical and Food Safety Bureau,
Ministry of Health, Labour and Welfare
Translated by
Pharmaceuticals and Medical Devices Agency
Pharmaceutical and Food Safety Bureau,
Ministry of Health, Labour and Welfare
1-2-2 Kasumigaseki, Chiyoda-ku, Tokyo
100-8916 Japan
Office of Safety I,
Pharmaceuticals and Medical Devices Agency
3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo
100-0013 Japan
E-mail: [email protected]
This English version of PMDSI is intended to be a reference material to provide convenience for users. In the event
of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA
shall not be responsible for any consequence resulting from use of this English version.
Pharmaceuticals and
Medical Devices
Safety Information
No. 281
July 2011
Pharmaceutical and Food Safety Bureau,
Ministry of Health, Labour and Welfare, Japan
Outline of Information
No.
Subject
Measures
1
Revision of Package
Inserts of Subcutaneous
Port and Catheter
P
2
Freeze-dried Live
Attenuated Measles
Vaccine (and 4 others)
P
C
3
4
Cortisone Acetate
(and 9 others)
List of Products Subject
to Early Post-marketing
Phase Vigilance
D: Distribution of Dear Healthcare Professional Letters
Pharmaceuticals and Medical Devices
Safety Information No. 281
Outline of Information
A subcutaneous port and catheter is an implantable
medical device used for delivering drugs, etc into a
blood vessel.
Catheter disconnection from the port as well as
catheter fracture and breakage on the port connector
or between the first rib and the clavicle have been
reported in patients using these devices.
Accordingly, MHLW required the marketing
authorization holders (MAHs) to revise the
Warnings and other sections of the package inserts.
The details are described in this section.
This section presents the contents of the revisions
and case summaries that served as the basis for
these revisions to important adverse reactions
included under the Precautions section of package
inserts of drugs that have been revised in
accordance with the Notification dated May 31,
2011.
Page
5
8
Revision of Precautions (No. 227)
20
List products subject to Early Post-marketing Phase
Vigilance as of July 1, 2011.
24
P: Revision of Precautions
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C: Case Reports
July 2011
PMDA medi-navi (Pharmaceuticals and Medical Devices
Information E-mail Alert Service)
The PMDA is providing the “PMDA medi-navi” a Pharmaceuticals and Medical Devices Information
E-mail Alert Service (only available in Japanese language), when important safety information
regarding pharmaceuticals and medical devices including Dear Healthcare Professional Letters or
Revision of Precautions is issued. This e-mail service will enable you to obtain safety information
faster and more efficiently, free of charge. Please feel free to use this service for your faster
information collection.
See our website for details of the service.  http://www.info.pmda.go.jp/info/idx-push.html
Reporting of safety information such as adverse reactions
to the Minister of Health, Labour and Welfare is a duty of
medical and pharmaceutical providers.
If medical and pharmaceutical providers such as physicians, dentists, and pharmacists detect adverse
reactions, infections associated with drugs or medical devices, or medical device adverse events, it is
mandatory for such providers to report them to the Minister of Health, Labour and Welfare directly or
through the marketing authorization holder. As medical and pharmaceutical providers, drugstore and
pharmacy personnel are also required to report safety issues related to drugs and medical devices.
Pharmaceuticals and Medical Devices
Safety Information No. 281
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July 2011
Abbreviations
ADEM
ADRs
Al-P
ALT (GPT)
AST (GOT)
BE
BUN
CHDF
CRP
CT
div
eGFR
EPPV
FY
HbA1c
HCO3
HBs
IU
JDS
KL-6
LDH
MAH
MRI
Na
O2sat
PCO2
PO2
PEG
pH
PLT
PT
RBC
RR
S2
SpO2
SPECT
TACE
Vp1
WBC
-GTP
Acute disseminated encephalomyelitis
Adverse drug reactions
Alkaline phosphatase
Alanine aminotransferase (Glutamate pyruvate transaminase)
Aspartate aminotransferase (Glutamate oxaloacetate transaminase)
Base excess
Blood urea nitrogen
Continuous haemodiafiltration
C-reactive protein
Computed tomography
Intravenous drip
estimated glomerular filtration rate
Early Post-marketing Phase Vigilance
Fiscal year
Hemoglobin A1c
Bicarbonate
Hepatitis B surface
International unit
Japan Diabetes Society
Sialylated carbohydrate antigen KL-6 (Krebs von den Lunge-6)
Lactate dehydrogenase
Marketing authorization holder
Magnetic resonance imaging
Sodium
Oxygen saturation
Arterial carbon dioxide partial pressure
Arterial oxygen partial pressure
Percutaneous endoscopic gastrostomy
Hydrogen ion concentration
Platelet
Prothrombin Time
Red blood cell count
Respiratory rate
Segment 2 (Left posterior lateral segment of liver)
Oxygen saturation
Single photon emission computed tomography
Transcatheter arterial chemoembolization
Invasion of distal to second order branches of the portal vein
White blood cell count
gamma-glutamyl transpeptidase
Pharmaceuticals and Medical Devices
Safety Information No. 281
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July 2011
1
Revision of Package Inserts of Subcutaneous
Port and Catheter
1.
Introduction
A subcutaneous port and catheter is a medical device which consists of an injection port with a
self-sealing septum connected to a catheter. It has a subcutaneously implanted port and a catheter
placed in the subclavian vein, cubital vein or hepatic artery (Table) that can be for short-term or
long-term use, and it is used for the administration of systemic chemotherapy and nutritional
management.
Catheter fracture/breakage, port body breakage, and catheter disconnection from the port have
been reported in patients using these devices. In some cases, the fractured catheter migrated into the
heart or the pulmonary artery. Based on the above, precautions for use of subcutaneous port and
catheter are added to the “Warnings” and the “Precautions” sections of the package insert. The details
are described below.
Table
List of subcutaneous port and catheter
MAHs
Brand Name
Akita Sumitomo
Bakelite Co., Ltd.
 SEPTUM PORT CATHETER
 SEPTUM PORT CATHETER (Aero type, Aero mini type)
Cook Japan Inc.
 Vital-Port
 Titanium Vital-Port
Create Medic Co., Ltd.
 Cliny Port System (MRI Type)
 Cliny Port System (MRI Type, For Intravenous PUR 5Fr / 6Fr Catheter)
Sata Corporation
 SOPH-A-PORT
Terumo Clinical
Supply Co., Ltd.
 TherdicaPort
Toray Industries, Inc.





AnthronP-U Catheter
P-U Celsite Port (Kit)
P-U Celsite Port (Discreet kit)
P-U Celsite Port (Kit for intravenous use only)
P-U Celsite Port (Port only)
Nipro Corporation




Infuser Port
Catheter Access
Catheter Access P (Regular type)
Catheter Access P (Regular type, Separate, for 2.7Fr)
 Catheter Access AI Kit
 Interflex AI Catheter (Catheter coated by heparin)
Nippon Sherwood
Medical Industries Ltd.
 Dermaport PP
Pharmaceuticals and Medical Devices
Safety Information No. 281
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July 2011
Piolax Medical
Devices, Inc.
 Piolax W Spiral Catheter
 Piolax W Spiral Catheter (G Spiral)
 Piolax W Spiral Catheter (Coaxial)
 IV Catheter
Medicon,Inc.
 M.R.I. Plastic Low Profile Port with attachable open-ended silicone 6.6 Fr.
Catheter
 MRI Implantable port with Groshong catheter
 MRI Port with Arterial 6.7 Fr. ChronoFlex catheter
 MRI Low Profile Port with TORAY Cathlock
 Titanim Low Profile Port with attachable Groshong 8.0 Frech catehter
 SlimPort M.R.I. Ultra Low Profile plastic port with attachable open ended
ChronoFlex 6.0 Fr. catheter
 X-PORT Low Profile Port with TORAY
 X-Port isp M.R.I. plastic port with attachable Groshong 8.0 Fr. catheter
 X-Port isp M.R.I. plastic port with attachable open ended ChronoFlex 6.0
Fr. catheter
Unitika Ltd.
 UK-Catheter kit (Catheter for Reservoir)
2.
Defect reports on port and catheter
A total of 740 cases of port and catheter defects have been reported for 12 products of 6
marketing authorization holders (MAHs) between April 2004 and December 2010.
Of these, 484 cases (65.4%) involved catheter fracture/breakage. These were observed on the
port connector in 275 cases, near the port connector in 15 cases, between the first rib and the clavicle
in 16 cases, at the elbow in 8 cases, at other sites in 12 cases and at unspecified sites in 158 cases. On
the other hand, 392 cases of those were reported that the fractured catheter migrated into the heart or
the pulmonary artery. Other than catheter fracture/breakage, 182 cases of port body breakage and 51
cases of catheter disconnection from the port were reported.
Catheter fracture/breakage may be attributed to multiple factors, including the port-catheter
connecting procedure and the physical stress on the port connector due to body movement or the
cardiac pulsation of patients with long-term use of these devices. Fracture of catheters pinched
between the first rib and the clavicle may be due to the surgical technique of catheter placement in the
subclavian vein. Catheter fracture at other sites may also be caused by continual physical stress due to
bending and extending of the arm of patients with long-term use. Catheter disconnection may be
attributed to inadequate port-catheter connection at the time of placement as well as increased pressure
in the port due to the use of a syringe less than 10mL in size to inject drugs.
3.
Safety measures
In light of the above-mentioned accidents, the MAHs have been improving their products (e.g.,
modification of port-catheter connection and improvement of connector parts). Meanwhile, to increase
caution for the catheter placement procedure and long-term use, MHLW issued a notification on May
25, 2011 and required the MAHs to include the following precautions in the “Warnings” and
“Precautions” sections of package inserts.
 There is a risk of catheter fracture or other adverse events associated with long-term use of the
device.
 Consider removal from patients for whom the placements of the devices are no longer needed.
 Use an appropriate-sized syringe for flushing.
 There are possible risks associated with the use of a subcutaneous port and catheter.
Specifically, the "Warnings" and the “Precautions” sections have been revised as follows. Take
the following precautions and follow-up patients carefully when using a subcutaneous port and
catheter.
Pharmaceuticals and Medical Devices
Safety Information No. 281
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July 2011
 The “Warnings” section should include the following precautions:
(1) When placing a catheter in the subclavian vein, make sure not to be pinched between the first
rib and the clavicle. [Catheter fracture or occlusion may occur.]
(2) Catheter fracture or migration into the heart may occur associated with long-term use. Removal
of this product is recommended, if continuous use of this product is not medically necessary and
it can be removed safely, after considering the patient's risk.
 In the “Precautions” section, the following precaution (1) should be included in the “Important
Precautions”, and the following precaution (2) should be included in the “Defects and Adverse
Events”.
(1) Use an XX mL or larger size of syringe (the appropriate size should be designated based on the
validation test of individual products by the MAH) when injecting drugs into the port chamber
or flushing the catheter. [If a syringe less than XX mL is used, the pressure in the port chamber
may increase and cause damage,etc. to the port or catheter.]
(2) The following are possible risks associated with the use of a subcutaneous port and catheter.
Caution should be exerted to these risks at the time of follow-up of patients.
 Port migration or reversal
 Port body breakage
 Septum breakage
 Infection around the implanted site
 Hematoma around the implanted site
 Catheter disconnection from the port
 Catheter perforation
 Catheter fracture
 Catheter migration into a blood vessel
 Catheter occlusion
 Catheter-deployed venous occlusion
 Fibrin sheath
 Subcutaneous extravasation of drug
 System-associated infection
 Skin disorder around the puncture site
 Pulmonary thromboembolism
Pharmaceuticals and Medical Devices
Safety Information No. 281
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July 2011
2
Important Safety Information
This section presents the contents of revisions and case summaries that served as the basis for
these revisions to important adverse reactions included under the Precautions section of the package
inserts of drugs that have been revised in accordance with the Notification dated May 31, 2011.
1
Freeze-dried Live Attenuated Measles Vaccine; Freeze-dried
Live Attenuated Measles, Rubella Combined Vaccine
Freeze-dried Live Attenuated Measles Vaccine
DRIED LIVE ATTENUATED MEASLES VACCINE (SCHWARZ FF-8
STRAIN) "Takeda" (Takeda Pharmaceutical Company Limited)
Freeze-dried Live Attenuated Measles Virus Vaccine
"Kitasatodaiichisankyo" (Kitasato Daiichi Sankyo Vaccine Co., Ltd.)
MEASLES VIRUS VACCINE LIVE ATTENUATED "BIKEN CAM"
(The Research Foundation for Microbial Diseases of Osaka University)
Freeze-dried Live Attenuated Measles, Rubella Combined Vaccine
FREEZE-DRIED LIVE ATTENUATED MEASLES AND RUBELLA
COMBINED VACCINE (SCHWARZ FF-8 STRAIN/TO-336 STRAIN)
"Takeda" (Takeda Pharmaceutical Company Limited)
Freeze-dried Live Attenuated Measles, Rubella Combined Vaccine
"Kitasatodaiichisankyo" (Kitasato Daiichi Sankyo Vaccine Co., Ltd.)
MEARUBIK (The Research Foundation for Microbial Diseases of Osaka
University)
Vaccines, Mixed biological preparations
Freeze-dried Live Attenuated Measles Vaccine
Use for prevention of measles.
Freeze-dried Live Attenuated Measles, Rubella Combined Vaccine
Use for prevention of measles and rubella.
Brand Name
(name of company)
Therapeutic Category
Indications
PRECAUTIONS (underlined parts are revised)
Adverse Reactions
(clinically significant
adverse reactions)
Acute disseminated encephalomyelitis (ADEM): Acute disseminated
encephalomyelitis (ADEM) may occur. In such cases, pyrexia, headache, convulsion,
movement disorder, and disturbed consciousness generally occur within several days
to 2 weeks after vaccination. If ADEM is suspected, the patients should be diagnosed
using MRI etc., and appropriate measures should be taken.
Encephalitis/encephalopathy: Encephalitis or encephalopathy may occur. Patients
should be carefully monitored. If any abnormalities are observed, the patients should
be diagnosed using MRI etc., and appropriate measures should be taken.
Reference
Information
Freeze-dried Live Attenuated Measles Vaccine
The number of reported adverse reactions (for which a causality to the vaccine could
not be ruled out) for the past 3 years (April 1, 2008 to April 30, 2011)
 Acute disseminated encephalomyelitis: 2 cases (no fatal cases)
The number of patients using this vaccine per year estimated by MAHs:
Approximately 76,000 (2010)
Launched in Japan: June 1971
Freeze-dried Live Attenuated Measles, Rubella Combined Vaccine
Pharmaceuticals and Medical Devices
Safety Information No. 281
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July 2011
The number of reported adverse reactions (for which a causality to the vaccine could
not be ruled out) for the past 3 years (April 1, 2008 to April 30, 2011)
 Encephalopathies: 6 cases (no fatal cases)
The number of patients using this vaccine per year estimated by MAHs:
approximately 4,600,000 (2010)
Launched in Japan: December 2005
Case Summary
<Freeze-dried Live Attenuated Measles Vaccine>
Patient
Adverse reactions
Daily dose/
No.
Sex/
Reason for use Treatment
Clinical course and therapeutic measures
duration
Age
(complications)
1
Female Measles
0.5 mL
Acute disseminated encephalomyelitis
immunization Once
Day of vaccination:
10s
(none)
The patient received freeze-dried live attenuated measles
vaccine.
18 days after vaccination:
During softball club activities, she suddenly experienced glare
in both eyes and lost consciousness. Afterwards, she returned
to consciousness and went back home.
At home, she was found foaming at the mouth on her bed, with
a flushed face and ankylosis. She was then transferred to
Hospital A by ambulance.
Following this, systemic tonic convulsion starting with
numbness of the left hand and twitching of the left eyelid was
observed 6 times in total.
27 days after vaccination:
The patient was transferred to Hospital B.
Cerebrospinal fluid cell count and neopterin increased. The
single photon emission computed tomography (SPECT)
showed an increased cerebral blood flow in the lesion. She was
diagnosed with secondary encephalitis (acute disseminated
encephalomyelitis). Steroid pulse therapy, human
immunoglobulin therapy, and post-steroid therapy (oral) were
performed. During the treatment course, continuous
administration of midazolam and oral administration of sodium
valproate and gabapentin were required to control convulsive
seizure.
Oral administration of gabapentin was continued.
57 days after vaccination:
The symptoms remitted and the patient was discharged from
the hospital.
Concomitant medications: none
<Freeze-dried Live Attenuated Measles, Rubella Combined Vaccine>
Patient
Adverse reactions
Daily dose/
No.
Sex/
Reason for use Treatment
Clinical course and therapeutic measures
duration
Age
(complications)
2
Male Prevention of 0.5 mL
Acute encephalopathy
Under measles and
Day of vaccination:
Once
age of rubella
The patient received freeze-dried live attenuated measles,
(none)
10
rubella combined vaccine.
Day 9 of vaccination:
The patient had pyrexia of 39°C and vomited once in the
evening.
Pharmaceuticals and Medical Devices
Safety Information No. 281
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July 2011
Day 10 of vaccination:
The patient had pyrexia between 37.7°C to 38.2°C in the
morning. He visited the reporting hospital. Cough (-), nasal
discharge (-). Only mild redness of pharynx was noted. He had
appetite and felt healthy. Blood test results were normal. Since
pyrexia was considered to be caused by the vaccine, no
medications were given.
Convulsive status epilepticus was observed at night and he was
admitted to another Hospital A.
Unknown date:
After admission, convulsion persisted for 4 - 5 days, with
disturbed consciousness. The patient was diagnosed with acute
encephalopathy based on an MRI scan.
Day 26 of vaccination:
The consciousness returned, but rigidity of limbs was noted.
(Information about the patient’s clinical course was obtained
from Doctor A at the other hospital by a phone call).
Day 77 of vaccination:
The patient was discharged from another Hospital A. He
started rehabilitation at another Hospital B.
Day 189 of vaccination:
The patient recovered, but with sequelae (rigidity of limbs and
unsteady neck).
Concomitant medications: none
2
Cisplatin (intra-arterial injection)
Brand Name
(name of company)
Therapeutic Category
Indications
IA-call for Intra-arterial Injection 50 mg, 100 mg
(Nippon Kayaku Co., Ltd.)
Antineoplastics-Miscellaneous
Hepatocellular carcinoma
PRECAUTIONS (underlined parts are revised)
Adverse Reactions
(clinically significant
adverse reactions)
Hepatobiliary disorders: Hepatobiliary disorders including cholecystitis, biloma,
and liver abscess may occur. Patients should be carefully monitored, and if any
abnormalities are observed, appropriate measures should be taken.
Reference
Information
The number of reported adverse reactions (for which a causality to the drug could not
be ruled out) for the past 3 years (April 1, 2008 to April 6, 2011)
 Hepatobiliary disorders: 7 cases (no fatal cases)
The number of patients using this drug per year estimated by MAHs: Approximately
7,300 (FY 2010)
Launched in Japan: July 2004
Case Summary
Patient
No.
Sex/
Age
Reason for use
(complications)
1
Male
80s
Hepatocellular
carcinoma
[Stage III:
(alcoholic
Pharmaceuticals and Medical Devices
Safety Information No. 281
Daily
dose/
Treatment
duration
80 mg for
1 day
Adverse reactions
Clinical course and therapeutic measures
Liver abscess (multiple)
Medical history: Large intestine carcinoma
The patient received transcatheter arterial chemoembolization
(TACE) with cisplatin 100 mg about 7 months and 3 months
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July 2011
hepatopathy,
lung cancer
[Stage II])
Pharmaceuticals and Medical Devices
Safety Information No. 281
before administration. Ethanol 10 mL was injected when the
second TACE was performed.
Day 1 of administration:
Cisplatin 80 mg was administered for multiple hepatocellular
carcinoma (TACE was performed).
Cefotiam hydrochloride 1 g was administered.
1 day after administration:
Cefotiam hydrochloride 2 g (2 ×) was administered (for 3
days).
4 days after administration:
Cefotiam hydrochloride 1g and meropenem hydrate 0.5 g were
administered.
5 days after administration:
Meropenem hydrate 1 g (2 ×) was administered.
6 days after administration:
Meropenem hydrate 2.5 g (5 ×) was administered.
7 days after administration:
Meropenem hydrate 2 g (4 ×) and vancomycin hydrochloride
1g (2 ×) were administered.
8 days after administration:
Vancomycin hydrochloride 1g was administered (for 10 days).
After TACE, antibiotics were administered for prevention of
infection, but inflammatory reaction occurred and did not
remit.
13 days after administration:
An abdominal CT showed air density in the liver carcinoma
where TACE was performed.
Liver abscess (multiple) developed. Administration of
antibiotics was continued, but the symptoms did not remit.
17 days after administration:
Abscess drainage was performed.
19 days after administration:
Vancomycin hydrochloride 1g was administered (for 6 days).
21 days after administration:
Clindamycin 600 mg was administered.
22 days after administration:
Clindamycin 1800 mg (3 ×) was administered (for 5 days).
25 days after administration:
Vancomycin hydrochloride 0.75 g was administered (for 3
days).
26 days after administration:
Gentamicin sulfate 20 mg (intravenous drip [div]) and 180 mg
(div) was administered.
27 days after administration:
Clindamycin 1200 mg (2 ×) and itraconazole 20 mL (for 8
days) were administered.
28 days after administration:
Abscess drainage was performed.
During the drainage, CRP was elevated up to 17.6 mg/dL.
32 days after administration:
Meropenem hydrate 0.5 g and linezolid 600 mg were
administered.
33 days after administration:
Meropenem hydrate 1.5 g (3 ×) (for 17 days) and linezolid
1200 mg (2 ×) (for 4 days) were administered.
36 days after administration:
Gentamicin sulfate 10 mg was infused into abscess (for 3
days).
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July 2011
38 days after administration:
Linezolid 1200 mg (2 ×) was administered (for 12 days).
40 days after administration:
Itraconazole 20 mL was administered (for 10 days).
50 days after administration:
Meropenem hydrate 1 g (2 ×) (for 2 days) and linezolid
600 mg were administered.
51 days after administration:
Linezolid 1200 mg (2 ×) was administered (for 28 days).
52 days after administration:
Meropenem hydrate 1.5 g (3 ×) was administered (for 27
days).
62 days after administration:
CRP was decreased to 3.6 mg/dL.
71 days after administration:
After having returned to hospital following staying out
overnight, he developed pneumonia aspiration.
79 days after administration:
Respiratory failure progressed, and the patient died.
Concomitant medications: gelatin, epirubicin hydrochloride, mitomycin C, iodine addition products of the
ethylesters of the fatty acids obtained from poppyseed oil, ramosetron hydrochloride, pentazocine,
alprostadil, iohexol
Patient
No.
Sex/
Age
Reason for use
(complications)
2
Male
70s
Hepatocellular
carcinoma
[Stage IVA]
(hepatitis C,
hepatic
cirrhosis)
Pharmaceuticals and Medical Devices
Safety Information No. 281
Daily
dose/
Treatment
duration
60 mg
for 1 day
Adverse reactions
Clinical course and therapeutic measures
Biloma, Liver abscess
The patient developed multiple tumor stains measuring 10 to 20
mm in the right lobe of his liver. The stage of the portal vein
invasion was Vp1. A tumor stain measuring 45 mm was
showed in S2.
Day 1 of administration:
Cisplatin 30 mg and the iodine addition product of the
ethylesters of the fatty acids obtained from poppyseed oil were
administered intra-arterially via left hepatic artery, and
embolization was performed with gelatin.
Cisplatin 30 mg and the iodine addition product of the
ethylesters of the fatty acids obtained from poppyseed oil were
injected into the posterior segmental branch of the dominant
right hepatic artery.
9 days after administration:
CRP was as high as 10.03 mg/dL. A follow-up observation was
performed.
14 days after administration:
CRP was 5.6 mg/dL.
17 days after administration:
The patient was temporally discharged from the hospital.
19 days after administration:
Pyrexia developed, and biloma was noted in the right lobe and
the caudate lobe on images.
CRP was elevated again to 8.37 mg/dL. WBC was 10200/μL.
26 days after administration:
Biloma increased in both lobes. Liver abscess developed.
28 days after administration:
The patient was treated with oral levofloxacin hydrate 600
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July 2011
mg/day (for 4 days), but his symptoms could not be controlled.
31 days after administration:
The patient was admitted to the hospital. A CT showed an
increased liver abscess. Sulbactam sodium and cefoperazone
sodium 4 g/day were administered (for 19 days).
51 days after administration:
Inflammatory reaction was slightly improved, and the patient
was discharged from the hospital.
79 days after administration:
CRP was 7.78 mg/dL. Biloma and liver abscess had not
resolved.
Approximately 7 months after administration:
Biloma and liver abscess had not resolved. The patient died of
the primary disease.
Concomitant medications: iodine addition products of the ethylesters of the fatty acids obtained from
poppyseed oil, gelatin
3
Sitagliptin Phosphate Hydrate
GLACTIV Tablets 25 mg, 50 mg, 100 mg (Ono Pharmaceutical Co., Ltd.)
JANUVIA Tablets 25 mg, 50 mg, 100 mg (MSD K.K.)
Antidiabetic agents
Type 2 diabetes mellitus
To be used only when the patient does not sufficiently respond to one of the
following treatment:
(1) Diet and exercise therapies alone
(2) Sulfonylurea along with diet and exercise therapies
(3) Thiazolidine along with diet and exercise therapies
(4) Biguanide along with diet and exercise therapies
(5) α-glucosidase inhibitor along with diet and exercise therapies
Brand Name
(name of company)
Therapeutic Category
Indications
PRECAUTIONS (underlined parts are revised)
Adverse Reactions
(clinically significant
adverse reactions)
Interstitial pneumonia: Interstitial pneumonia may occur. If pyrexia, cough,
dyspnoea or abnormal chest sound (crepitations), etc. are observed, examinations
including chest X-ray, chest CT scan, and serum marker test should be performed. If
interstitial pneumonia is suspected, administration of this drug should be
discontinued, and appropriate measures including administration of corticosteroids
should be taken.
Reference
Information
The number of reported adverse reactions (for which a causality to the drug could not
be ruled out) for the past 1 year and 5 months (from initial marketing to April 30,
2011)
 Interstitial pneumonia: 6 cases (no fatal cases)
The number of patients using this drug per year estimated by MAHs: approximately
630,000 (May 2010 to April 2010)
Launched in Japan: December 2009
Case Summary
No.
1
Patient
Sex/
Reason for use
Age
(complications)
Female Diabetes
Pharmaceuticals and Medical Devices
Safety Information No. 281
Daily dose/
Treatment
duration
50 mg for
Adverse reactions
Clinical course and therapeutic measures
Interstitial pneumonia
- 13 -
July 2011
mellitus
(tobacco
user,
hypertension)
34 days
Day 1 of administration:
The patient started receiving sitagliptin phosphate hydrate.
Within several days of administration:
The patient became aware of dyspnoea.
Day 33 of administration:
Dyspnoea gradually progressed. The patient was admitted to
the hospital for the purpose of bronchoscopy.
Day 34 of administration (day of discontinuation):
A CT showed an obvious image of interstitial pneumonia in the
lung fields. Steroid pulse therapy (60 mg for 3 days) was
started. Administration of sitagliptin phosphate hydrate was
discontinued.
6 days after discontinuation:
KL-6 2084 U/mL, LDH 394 IU/L, CRP 5.4 mg/dL.
40 days after discontinuation:
Interstitial pneumonia remitted. Steroid 30 mg/day being
administered. LDH 167 IU/L.
44 days after discontinuation:
KL-6 1457 U/mL.
Concomitant medications: telmisartan, saikanto, goshuyuto
60s
Laboratory Examination
7800
2 days
after
discontinua
tion
9000
4 days
after
discontinua
tion
8400
6 days
after
discontinua
tion
8900
11 days
after
discontinua
tion
8700
40 days
after
discontinua
tion
―
44 days
after
discontinua
tion
―
12.3
12.3
12.1
12.4
12.8
―
―
47.7
2.91
67.5
―
―
53.2
3.14
―
―
―
47.2
3.48
―
―
―
42.8
5.4
64
2084
394
49.8
0.9
―
―
―
―
―
―
―
167
―
―
―
1457
―
1 day after
discontinua
tion
WBC (/L)
Hemoglobin
(g/dL)
PLT (104/L)
CRP (mg/dL)
PT (%)
KL-6 (U/mL)
LDH (IU/L)
4
Sorafenib Tosilate
Brand Name
(name of company)
Therapeutic Category
Nexavar Tablet 200 mg
(Bayer Yakuhin, Ltd.)
Antineoplastics-Miscellaneous
Radically unresectable or metastatic renal cell carcinoma, unresectable
hepatocellular carcinoma
Indications
PRECAUTIONS (underlined parts are revised)
Adverse Reactions
(clinically significant
adverse reactions)
Fulminant hepatitis, hepatic dysfunction/jaundice, hepatic failure, hepatic
encephalopathy: Fulminant hepatitis, hepatic dysfunction with elevations of AST
(GOT) or ALT (GPT), jaundice, hepatic failure, or hepatic encephalopathy may
occur. Patients should be carefully monitored. If abnormalities are observed, the dose
of this drug should be reduced or administration of this drug should be suspended
and discontinued, and appropriate measures should be taken. Hepatic encephalopathy
has been reported mainly in patients with hepatocellular carcinoma or hepatic
cirrhosis. When administering this drug to such patients, they should be carefully
Pharmaceuticals and Medical Devices
Safety Information No. 281
- 14 -
July 2011
monitored for changes in their clinical symptoms including disturbed consciousness.
Haemorrhagic enterocolitis and ischaemic enterocolitis: Serious enterocolitis
including haemorrhagic enterocolitis and ischaemic enterocolitis may occur. Patients
should be carefully monitored, and if symptoms including severe abdominal pain,
diarrhoea, or bloody stool are observed, administration of this drug should be
discontinued, and appropriate measures should be taken.
Reference
Information
The number of reported adverse reactions (for which a causality to the drug could not
be ruled out) for the past 3 years (from initial marketing to April 10, 2011)
 Fulminant hepatitis: 2 cases (2 fatal cases)
 Haemorrhagic enterocolitis, ischaemic enterocolitis: 7 cases (no fatal cases)
The number of patients using this drug per year estimated by MAHs: Approximately
6,000 (June 2010 to May 2011)
Launched in Japan: April 2008
Case Summary
Patient
No.
Sex/
Age
Reason for use
(complications)
1
Male
70s
Right renal
cancer
(hyperuricaemia,
hypertension,
metastases to
lymph nodes,
metastatic lung
cancer)
Daily
dose/
Treatment
duration
800 mg
for
100 days
Adverse reactions
Clinical course and therapeutic measures
Fulminant hepatitis
Day 1 of administration:
The patient started receiving sorafenib tosilate.
Day 100 of administration (day of discontinuation):
Fulminant hepatitis developed. Administration of sorafenib
tosilate was discontinued.
Administration of glycyrrhizin/DL-methionine and
ursodeoxycholic acid was started. Jaundice and hepatic
encephalopathy occurred (Grade 2).
12 days after discontinuation:
Jaundice worsened.
14 days after discontinuation:
Renal failure occurred.
16 days after discontinuation:
Haemodialysis and bilirubin adsorption were performed.
22 days after discontinuation:
Decreased level of consciousness was observed early in the
morning. Haemodialysis and bilirubin adsorption were
scheduled but canceled.
Around noon, the patient died of hepatic failure.
Abdominal CT test: (Day 94 of administration) Metastasis to
liver was not confirmed, Gallbladder: Swelling was noted.
Abdominal ultrasonography: (15 days after discontinuation)
Liver: Mild uneven surface, Gallbladder: circumferential
thickening.
Concomitant medications: none
Laboratory Examination
Albumin (g/dL)
Total bilirubin
(mg/dL)
7 days
before
administration
Day 14 of
administration
Day 42 of
administration
Day 72 of
administration
Day 100 of
administrat
ion (day of
discontinuation)
5 days
after
discontinuation
15 days
after
discontinuation
22 days
after
discontinuation
4.0
4.1
4.4
4.5
3.9
3.2
2.4
2.5
0.5
0.6
0.6
0.5
5.1
8.2
19.0
23.1
Pharmaceuticals and Medical Devices
Safety Information No. 281
- 15 -
July 2011
AST (GOT) (IU/L)
ALT (GPT) (IU/L）
LDH (IU/L)
Al-P (IU/L)
-GTP (IU/L)
Ammonia (µg/dL)
PT activity (%)
5
21
20
205
256
19
30
27
360
260
29
132
240
352
331
68
86
135
295
266
60
―
99
―
102
―
103
―
105
2204
2388
1085
769
490
133
63
1257
1432
568
696
459
446
441
337
575
192
―
73
―
51
59
111
608
407
276
126
20
Metformin Hydrochloride (products with “Dosage and
Administration” of maximum daily dosage of 2250mg)
Brand Name
(name of company)
Therapeutic Category
METGLUCO Tablets 250 mg
(Dainippon Sumitomo Pharma Co., Ltd.)
Antidiabetic agents
Type 2 diabetes mellitus
To be used only when the patient does not sufficiently respond to one of the
following treatments:
(1) Diet and exercise therapies alone
(2) Sulfonylurea along with diet and exercise therapies
Indications
PRECAUTIONS (underlined parts are revised)
Important
Precautions
Lactic acidosis may occur due to dehydration. If any symptoms of dehydration are
observed, administration of this drug should be discontinued, and appropriate
measures should be taken.
In patients with renal impairment, the excretion of this drug in the kidneys is
decreased, leading to increased blood concentration. Before and after treatment is
started, caution in regards to the following points should be exerted:
1) Patients should be carefully monitored for renal impairment and dosing
adjustment should be considered.
2) During administration of this drug, the renal function (eGFR, serum creatinine
level, etc.) should be checked periodically, or more frequently in patients
requiring careful follow-up observation, such as elderly patients. If renal function
is aggravated, administration of this drug should be discontinued, or the dose of
this drug should be reduced.
Reference
Information
The number of reported adverse reactions (for which a causality to the drug could not
be ruled out) for the past 1 year (from initial marketing to April 28, 2011)
 Lactic acidosis due to dehydration: 2 cases (1 fetal case)
 Lactic acidosis due to aggravated renal function: 1 case (no fatal case)
The number of patients using this drug per year estimated by MAHs: approximately
190,000 (June 2010 to May 2011)
Launched in Japan: May 2010
Case Summary
No.
1
Patient
Sex/
Reason for use
Age
(complications)
Female Diabetes
mellitus
80s
(Chronic
cholecystitis)
Pharmaceuticals and Medical Devices
Safety Information No. 281
Daily dose/
Treatment
duration
750 mg
for 22
days

1000 mg
Adverse reactions
Clinical course and therapeutic measures
Lactic acidosis, intestinal obstruction
About two and a half years before administration, the patient was
referred and admitted to the hospital because she became
bedridden due to sequelae of cerebral infarction (prolonged
disturbed consciousness, right hemiplegia, speech loss,
- 16 -
July 2011
for
33 days
Pharmaceuticals and Medical Devices
Safety Information No. 281
pseudobulbar palsy), right femoral neck fracture, diabetes
mellitus, and because gastrogavage via gastric fistula was
necessary for long-term continuous treatment.
At an early stage of hospitalization, blood glucose was controlled
with insulin. The dose of insulin was gradually decreased, and
from about one year and 11 months before administration of
METGLUCO Tablet, administration of glimepiride and
metformin hydrochloride was started. Administration of
glimepiride was discontinued about 11 months before
administration of METGLUCO Tablet, and metformin
hydrochloride alone was continued.
Day 1 of administration:
Metformin hydrochloride (750 mg/day) was switched to
METGLUCO Tablet 750 mg/day.
Day 23 of administration:
The dose of METGLUCO Tablet was increased to 1000
mg/day for improving glucose tolerance.
Day 49 of administration:
There was no finding of ileus when the gastric fistula catheter
was exchanged.
Day 54 of administration:
The patient vomited after enteral nutrition in the evening.
Percutaneous endoscopic gastrostomy (PEG) catheter was
opened, and there was drainage of 50 mL. Abdominal
distension was noted. Body temperature 36.5°C, pulse rate 126,
blood pressure 193/117 mmHg, SpO2 93%.
Day 55 of administration (day of discontinuation):
The patient vomited again after enteral nutrition in the
morning. PEG catheter was opened, and there was drainage of
60 mL in about 3 hours.
The patient was fasted in the daytime and drip infusion of
glucose-electrolyte solution 1000 mL was started.
In the afternoon, abdominal X-ray and other test results were
obtained. The patient was diagnosed with ileus and
dehydration, drip infusion of physiological saline solution 1000
mL diluted two-fold was added. Placement of bladder balloon
catheter, measurement of urine output, and twice-daily
measurement of blood glucose were instructed. Abdominal
distension was noted. Body temperature 36.3°C, pulse rate 108,
blood pressure 193/71 mmHg, SpO2 96%, respiratory rate (RR)
42.
Urine output measured was very small.
After 3 hours and 40 minutes, insulin 8 U was subcutaneously
administered due to a high level of blood glucose.
After 4 hours and 43 minutes, jaw breathing occurred.
Inhalation of oxygen 5 L/min was started.
After 4 hours and 55 minutes, administration of dopamine
hydrochloride was started due to blood pressure 40 mmHg
(palpation).
After 6 hours and 20 minutes, blood glucose level was
562 mg/dL.
After 6 hours and 30 minutes, body temperature 36.4°C, pulse
rate 120, blood pressure 80 mmHg (palpation), SpO 2 94%.
Urine output was small.
After 8 hours and 35 minutes, the patient was in
cardio-respiratory arrest. Cardiac massage was performed.
After 9 hours and 28 minutes, the patient died. (Cause of death:
lactic acidosis)
- 17 -
July 2011
Concomitant medications: aspirin, monoammonium glycyrrhizinate/glycine/DL-methionine, famotidine,
metoclopramide
Laboratory Examination
Blood glucose (mg/dL)
HbA1c (JDS level) (%)
BUN (mg/dL)
Serum creatinine
(mg/dL)
Total protein (g/dL)
RBC (× 104/mm3)
156
5.0
21.5
Approx. 1
year and 11
months
before
administration
95
―
19.8
0.53
0.71
0.83
0.74
0.80
1.73
6.8
496
6.2
―
6.8
513
6.6
540
6.8
512
8.6
626
Hemoglobin (g/dL)
15.6
―
16.6
16.4
16.5
20.3
Hematocrit (%)
Na (mEq/L)
45.4
139
―
138
48.4
142
49.5
143
49.2
140
62.1
138
Approx. 2.5
years before
administration
Arterial blood pH
PCO2 (mmHg)
PO2 (mmHg)
HCO3- (mM)
BE (mM)
O2sat (%)
Lactic acid (mg/dL)
Pyruvic acid (mg/dL)
No.
2
Sex/
Age
Male
90s
Approx. 11
months
before
administration
Approx. 5
months
before
administration
Day 21 of
administration
100
―
29.3
98
6.1
21.2
140
6.3
25.0
Day 55 of
administration
(day of
discontinuation)
576
―
47.5
Day 55 of administration
(day of discontinuation)
7.415
16.4
102.8
10.4
-10.4
97.7
91.4
3.77
Patient
Reason for use
(complications)
Diabetes
mellitus
(none)
Pharmaceuticals and Medical Devices
Safety Information No. 281
Daily dose/
Treatment
duration
750 mg
for
14 days

1500 mg
for
14 days

2250 mg
for
33 days
Adverse reactions
Clinical course and therapeutic measures
Lactic acidosis
From approximately 17 years before administration:
The patient had received oral medications for diabetes mellitus.
From approximately 2 months before administration:
The patient had received buformin hydrochloride 150 mg/day.
Day 1 of administration:
Blood glucose 257 mg/dL and HbA1c 6.0%. Buformin
hydrochloride was switched to METGLUCO Tablet 750
mg/day.
Serum creatinine was 1.3 mg/dL
Day 15 of administration:
Blood glucose 299 mg/dL. The dose of METGLUCO Tablet
was increased to 1500 mg/day.
Day 29 of administration:
Blood glucose 201 mg/dL. The dose of METGLUCO Tablet
was increased to 2250 mg/day.
Day 49 of administration:
Serum creatinine 1.6 mg/dL, HbA1c 6.9%
Day 60 of administration:
Dysarthria and perceptual disturbance on the left side of the
- 18 -
July 2011
body occurred. An MRI showed no abnormalities.
Fluid replacement 500 mL and methylmethionine sulfonium
chloride 400 mg were administered.
Day 61 of administration (day of discontinuation):
The patient was transferred to the hospital by ambulance due to
physical deconditioning.
Results of tests conducted at the hospital visit showed lactic
acid 157.9 mg/dL, pH 6.832, PCO2 9.0 mmHg, PO2 254.5
mmHg (reservoir 10L), base excess (BE) -32.5 mmol/L,
HCO3- 1.5 mmol/L. The patient was diagnosed with lactic
acidosis, and started inpatient care.
Administration of METGLUCO Tablet was discontinued.
Continuous haemodiafiltration (CHDF) was performed.
Blood concentration of metformin: 39300 ng/mL
2 days after discontinuation:
Lactic acid level was almost normal, and acidosis disappeared.
3 days after discontinuation:
CHDF was discontinued.
5 days after discontinuation:
Oral food intake was started. The patient was moved from the
intensive care unit to the general ward.
(Lactic acidosis resolved.)
Concomitant medications: none
Laboratory Examination
(The hospital where metformin hydrochloride was originally prescribed)
Fasting blood glucose level (mg/dL)
HbA1c (JDS level) (%)
BUN (mg/dL)
Serum creatinine (mg/dL)
RBC (× 104/mm3)
Hemoglobin (g/dL)
Hematocrit (%)
Day 1 of
administration
257
6.0
―
1.3
―
8.9
―
Day 49 of
administration
214
6.9
26
1.6
407
12.3
36.6
(Hospital where the patient was transported)
Fasting blood glucose level (mg/dL)
BUN (mg/dL)
Serum creatinine (mg/dL)
Serum lactic acid (mg/dL)
pH
BE (mmol/L)
RBC (× 104/mm3)
Hemoglobin (g/dL)
Hematocrit (%)
Na (mEq/L)
Pharmaceuticals and Medical Devices
Safety Information No. 281
Day 61 of
administration
(day of
discontinuation)
301
96
7.3
157.9
6.832
-32.5
414
12.9
40.4
141
1 day after
discontinuation
2 days after
discontinuation
3 days after
discontinuation
5 days after
discontinuation
29
68
4.5
120.6
7.453
-6.0
323
9.9
29.7
155
170
42
2.6
21.1
7.473
4.6
332
10.4
29.9
142
172
29
1.8
12.3
7.527
5.1
309
9.6
28.1
140
252
32
1.8
13.0
―
―
288
9.1
26.4
142
- 19 -
July 2011
3
Revision of Precautions
(No. 227)
This section presents details of revisions to the Precautions section of package inserts and brand names
of drugs that have been revised in accordance with the Notifications dated May 31, 2011 (excluding
those presented in 2. Important Safety Information of this Bulletin).
1
Adrenal hormone preparations
Cortisone Acetate
Dexamethasone (oral dosage form)
Dexamethasone Metasulfobenzoate Sodium
(injectable dosage form)
Dexamethasone Sodium Phosphate (injectable dosage form)
Triamcinolone
Triamcinolone Acetonide (injectable dosage form for intraarticular/
intramuscular/intradermal)
Hydrocortisone Sodium Phosphate
Fludrocortisone Acetate
Prednisolone (oral dosage form)
Prednisolone Sodium Succinate
Prednisolone Sodium Phosphate
Betamethasone
Betamethasone Acetate/Betamethasone Sodium Phosphate
Betamethasone Sodium Phosphate (injectable dosage form,
enema)
Brand Name
CORTONE Acetate Tablets 25 mg (Nichi-Iko Pharmaceutical Co., Ltd.)
DECADRON Tablets 0.5 mg (Nichi-Iko Pharmaceutical Co., Ltd.),
LenaDex Tablets 4 mg (Celgene K.K.)
MESADORON Injection 2 mg, 3 mg (Kobayashi Kako Co., Ltd.)
DECADRON Phosphate Injection 1.65 mg, 3.3 mg (MSD K.K.)
LEDERCORT Tablets 4 mg (Alfresa Pharma Corporation)
KENACORT-A INTRADERMAL INTRAARTICULAR Suspension Liquid
Injection 50 mg/5 m L (Bristol-Myers K.K.)
Hydrocortone Injection 100 mg, 500 mg (Aqueous)
(Nichi-Iko Pharmaceutical Co., Ltd.)
FLORINEF TABLETS 0.1mg (Bristol-Myers K.K.)
Predonine Tablets 5 mg (Shionogi & Co., Ltd.)
Predonine 10 mg, 20 mg, 50 mg (Aqueous) (Shionogi & Co., Ltd.)
PREDONEMA Enema 20 mg (Kyorin Pharmaceutical Co., Ltd.)
Rinderon Tablets 0.5 mg, Rinderon Powder 0.1%, Rinderon Syrup 0.01%, Rinderon
Suppository 0.5 mg, 1.0 mg (Shionogi & Co., Ltd.)
Pharmaceuticals and Medical Devices
Safety Information No. 281
- 20 -
July 2011
Rinderon Suspensions for Injection (Shionogi & Co., Ltd.)
Rinderon Injection 20 mg, 100 mg (Shionogi & Co., Ltd.),
STERONEMA ENEMA 3 mg, 1.5 mg (Nichi-Iko Pharma Factory Co., Ltd.)
Important
Precautions
Hepatitis may occur due to hepatitis B viral growth in hepatitis B virus carriers who
were administrated a corticosteroid. Attention for the occurrence of signs or
symptoms related to hepatitis B viral growth should be paid by continuously
monitoring results of liver function tests or hepatitis viral markers during and after
the administration period of this drug. If any abnormalities are observed, dose
reduction of this drug should be considered, and appropriate measures including
administration of an antiviral drug should be taken. In addition, hepatitis due to
hepatitis B virus has been reported in patients who were negative for HBs antigen
before the start of administration.
Adverse Reactions
(clinically significant
adverse reactions)
Induced infection or aggravated infection: Induced infection or aggravated
infection may occur. Hepatitis due to hepatitis B viral growth may occur. Patients
should be carefully monitored, and if any abnormalities are observed, appropriate
measures should be taken.
2
Adrenal hormone preparations
Dexamethasone Palmitate
Brand Name
Limethason INTRAVENOUS INJECTION 2.5 mg
(Mitsubishi Tanabe Pharma Corporation)
Important
Precautions
Hepatitis may occur due to hepatitis B viral growth in hepatitis B virus carriers who
were administrated a corticosteroid. Attention for the occurrence of signs or
symptoms related to hepatitis B viral growth should be paid by continuously
monitoring results of liver function tests or hepatitis viral markers during and after
the administration period of this drug. If any abnormalities are observed, dose
reduction of this drug should be considered, and appropriate measures including
administration of an antiviral drug should be taken. In addition, hepatitis due to
hepatitis B virus has been reported in patients who were negative for HBs antigen
before the start of administration.
Adverse Reactions
(clinically significant
adverse reactions)
Induced infection or aggravated infection: Induced infection or aggravated
infection may occur. Hepatitis due to hepatitis B viral growth may occur. Patients
should be carefully monitored, and if any abnormalities are observed, appropriate
measures should be taken.
3
Adrenal hormone preparations
Hydrocortisone
Brand Name
Cortril Tablets 10mg (Pfizer Japan Inc.)
Important
Precautions
Hepatitis may occur due to hepatitis B viral growth in hepatitis B virus carriers who
were administrated a corticosteroid. Attention for the occurrence of signs or
symptoms related to hepatitis B viral growth should be paid by continuously
monitoring results of liver function tests or hepatitis viral markers during and after
the administration period of this drug. If any abnormalities are observed, dose
reduction of this drug should be considered, and appropriate measures including
administration of an antiviral drug should be taken. In addition, hepatitis due to
hepatitis B virus has been reported in patients who were negative for HBs antigen
before the start of administration.
Adverse Reactions
(clinically significant
adverse reactions)
Infection: Induced infection or aggravated infection, etc. may occur. Hepatitis due to
hepatitis B viral growth may occur. Patients should be carefully monitored, and if any
abnormalities are observed, appropriate measures should be taken.
Pharmaceuticals and Medical Devices
Safety Information No. 281
- 21 -
July 2011
4
Adrenal hormone preparations
Hydrocortisone Sodium Succinate
Methylprednisolone
Methylprednisolone Sodium Succinate
Methylprednisolone Acetate
Brand Name
Solu-Cortef for Intravenous Use 250 mg, 500 mg, 1000 mg,
Solu-Cortef Injection 100 mg (Pfizer Japan Inc.)
Medrol Tablets 2 mg, 4 mg (Pfizer Japan Inc.)
Solu-Medrol for Intravenous Use 40 mg, 125 mg (Pfizer Japan Inc.)
Depo-Medrol Sterile Aqueous Suspension 20 mg, 40 mg (Pfizer Japan Inc.)
Important
Precautions
Hepatitis may occur due to hepatitis B viral growth in hepatitis B virus carriers who
were administrated a corticosteroid. Attention for the occurrence of signs or
symptoms related to hepatitis B viral growth should be paid by continuously
monitoring results of liver function tests or hepatitis viral markers during and after
the administration period of this drug. If any abnormalities are observed, dose
reduction of this drug should be considered, and appropriate measures including
administration of an antiviral drug should be taken. In addition, hepatitis due to
hepatitis B virus has been reported in patients who were negative for HBs antigen
before the start of administration.
Adverse Reactions
(clinically significant
adverse reactions)
Infection: Induction or masking of signs of infection, worsening of infection, etc.,
from viruses, bacteria, fungi, protozoa, or parasites may occur. It has been reported
that the incidence of these infections was elevated with a dose of corticosteroid.
Appropriate measures including antimicrobial drugs should be taken. Hepatitis due
to hepatitis B viral growth may occur. Patients should be carefully monitored, and if
any abnormalities are observed, appropriate measures should be taken.
5
Adrenal hormone preparations
Betamethasone/d-Chlorpheniramine Maleate
Brand Name
CELESTAMINE Combination Tablets, CELESTAMINE Combination Syrup
(MSD)
Important
Precautions
Hepatitis may occur due to hepatitis B viral growth in hepatitis B virus carriers who
were administrated a corticosteroid. Attention for the occurrence of signs or
symptoms related to hepatitis B viral growth should be paid by continuously
monitoring results of liver function tests or hepatitis viral markers during and after
the administration period of this drug. If any abnormalities are observed, dose
reduction of this drug should be considered, and appropriate measures including
administration of an antiviral drug should be taken. In addition, hepatitis due to
hepatitis B virus has been reported in patients who were negative for HBs antigen
before the start of administration.
Adverse Reactions
(clinically significant
adverse reactions)
Induced infection or aggravated infection: Induced infection or aggravated
infection may occur. Hepatitis due to hepatitis B viral growth may occur. Patients
should be carefully monitored, and if any abnormalities are observed, appropriate
measures should be taken.
6
Hormones-Miscellaneous
Mitotane
Brand Name
Opeprim (Yakult Honsha Co., Ltd.)
Pharmaceuticals and Medical Devices
Safety Information No. 281
- 22 -
July 2011
Adverse Reactions
(clinically significant
adverse reactions)
7
Hepatic dysfunction, jaundice: Hepatic dysfunction with significant elevations of
AST (GOT), ALT (GPT), γ-GTP, and Al-P or jaundice may occur. Patients should
be carefully monitored, and if any abnormalities are observed, appropriate measures
such as discontinuing administration should be taken.
Synthetic antibacterials
Linezolid
Brand Name
ZYVOX Tablets 600 mg, ZYVOX Injection 600 mg (Pfizer Japan Inc.)
Important
Precautions
Hyponatraemia may occur in association with administration of this drug. Patients
should be monitored by checking serum sodium level periodically. If any
abnormalities are observed, appropriate measures such as discontinuing
administration should be taken.
Adverse Reactions
(clinically significant
adverse reactions)
Hyponatraemia: Hyponatraemia associated with disturbed consciousness, queasy,
vomiting, anorexia, etc. may occur. If any abnormalities are observed, appropriate
measures such as discontinuing administration should be taken.
8
Vaccines
Freeze-dried, Cell Culture-derived Japanese Encephalitis
Vaccine (Inactivated) (ENCEVAC)
Brand Name
ENCEVAC for Subcutaneous Injection
(The Chemo-Sero-Therapeutic Research Institute)
Adverse Reactions
(clinically significant
adverse reactions)
Encephalitis/encephalopathy: Encephalitis/encephalopathy may occur. In such
cases, symptoms including pyrexia, quadriplegia, convulsion, and disturbed
consciousness may develop after vaccination. If encephalitis/encephalopathy is
suspected, diagnosis should be made by MRI etc., and appropriate measures should
be taken.
9
Vaccines
Freeze-dried, Cell Culture-derived Japanese Encephalitis
Vaccine (Inactivated) (JEBIK V)
Brand Name
JEBIK V (The Research Foundation for Microbial Diseases of Osaka University)
Adverse Reactions
(clinically significant
adverse reactions)
Encephalitis/encephalopathy: Encephalitis/encephalopathy may occur. In such
cases, symptoms including pyrexia, quadriplegia, convulsion, and disturbed
consciousness may develop after vaccination. If encephalitis/encephalopathy is
suspected, diagnosis should be made by MRI etc., and appropriate measures should
be taken.
10
Various functional testing reagents
Inulin
Brand Name
INULEAD Inj. (Fujiyakuhin Co., Ltd.)
Adverse Reactions
(clinically significant
adverse reactions)
Shock, anaphylactoid symptoms: Shock or anaphylactoid symptoms may occur.
Patients should be carefully monitored, and if abnormalities including dyspnoea or
decreased blood pressure are observed, administration of this drug should be
discontinued, and appropriate measures should be taken.
Pharmaceuticals and Medical Devices
Safety Information No. 281
- 23 -
July 2011
4
List of Products Subject to
Early Post-marketing Phase Vigilance
Early Post-marketing Phase Vigilance (EPPV) was established in 2001. This unique system for
new drugs refers to any safety assurance activities that are conducted within a period of 6 months just
after marketing of a new drug. It is imposed that its Marketing Authorization Holder is responsible for
collecting the adverse drug reactions (ADRs) from all of the medical institutions where the drugs are
used and for taking safety measures. The aim of the EPPV is to promote the rational proper use of the
drug in medical treatments, and to promptly take actions for prevention of the serious adverse drug
reactions. EPPV is specified as a condition of approval.
(As of July 1, 2011)
Nonproprietary name
Brand name
l-Menthol
MINCLEA catapasm for internal use 0.8%
Levofloxacin Hydrate
CRAVIT INTRAVENOUS DRIP INFUSION BAG
500 mg/100 mL, CRAVIT INTRAVENOUS DRIP
INFUSION 500 mg/20 mL
Paliperidone
Invega Tablets 3 mg, 6 mg, 9 mg
Ciclesonide
Alvesco 50 μg Inhaler 112 puffs, Alvesco 100 μg Inhaler
112 puffs, Alvesco 200 μg Inhaler 56 puffs*1
Roxatidine Acetate Hydrochloride
ALTAT CAPSULES 37.5, 75*1
Fentanyl
OneDuro Patch 0.84 mg, 1.7 mg, 3.4 mg, 5 mg, 6.7 mg
Azacitidine
Vidaza for Injection 100 mg
Fondaparinux Sodium
Arixtra Injection 5 mg, 7.5 mg
Ustekinumab (Genetical Recombination)
Stelara Subcutaneous Injection 45 mg Syringe
Dabigatran Etexilate Methanesulfonate
Prazaxa Capsules 75 mg, 110 mg
Galantamine Hydrobromide
REMINYL Tablets 4 mg, 8 mg, 12 mg, REMINYL OD
Tablets 4 mg, 8 mg, 12 mg, REMINYL Oral Solution
4 mg/mL
Eldecalcitol
EDIROL Capsule 0.5 g, 0.75 g
Freeze-dried, Cell Culture-Derived Japanese Encephalitis
Vaccine (Inactivated)
ENCEVAC Subcutaneous Injection
Pharmaceuticals and Medical Devices
Safety Information No. 281
- 24 -
Name of the marketing
authorization holder
Date of EPPV initiate
Nippon Pharmaceutical
Co., Ltd.
January 11, 2011
Daiichi Sankyo
Company, Limited
January 11, 2011
Janssen Pharmaceutical
K.K.
January 17, 2011
Teijin Pharma Limited
January 21, 2011
ASKA Pharmaceutical
Co., Ltd.
January 21, 2011
Janssen Pharmaceutical
K.K.
February 4, 2011
Nippon Shinyaku Co.,
Ltd.
March 11, 2011
GlaxoSmithKline K.K.
March 11, 2011
Janssen Pharmaceutical
K.K.
March 14, 2011
Nippon Boehringer
Ingelheim Co., Ltd.
March 14, 2011
Janssen Pharmaceutical
K.K.
March 22, 2011
Chugai Pharmaceutical
Co., Ltd.
April 11, 2011
The
Chemo-Sero-Therapeutic
Research Institute
April 11, 2011
July 2011
Romiplostim (Genetical Recombination)
Romiplate for s.c. injection 250 g
Anti-human Thymocyte Immunoglobulin, Rabbit
Thymoglobuline for Intravenous Infusion 25 mg*2
Doripenem Hydrate
FINIBAX for Drip Infusion 0.25 g, FINIBAX Kit for Drip
Infusion 0.25 g*3
Levobupivacaine Hydrochloride
POPSCAINE 0.25% inj. 25 mg/10mL, POPSCAINE 0.25%
inj. syringe 25 mg/10 mL*4
Repaglinide
SUREPOST Tablets 0.25 mg, 0.5 mg
Febuxostat
Feburic Tablets 10 mg, 20 mg, 40 mg
Levonorgestrel
NORLEVO 0.75 mg Tablet
Pioglitazone Hydrochloride/Glimepiride
SONIAS Combination Tablets LD&HD
Memantine Hydrochloride
MEMARY TABLETS 5 mg, 10 mg, 20 mg
Adalimumab (Genetical Recombination)
HUMIRA for s.c. injection syringe 40 mg/0.8 mL,
HUMIRA for s.c. injection syringe 20 mg/0.4 mL*5
Erlotinib Hydrochloride
TARCEVA Tablet 25 mg, 100 mg*6
Gabapentin
GABAPEN Tablets 200 mg, 300 mg, 400 mg*1
Peginterferon Alfa-2a (Genetical Recombination)
PEGASYS s.c. 90 μg, 180 μg*7
Lamotrigine
Lamictal Tablets 25 mg, 100 mg*8
Ribavirin
COPEGUS Tablet 200 mg*9
*1
*2
*3
*4
*5
*6
*7
*8
*9
Kyowa Hakko Kirin Co.,
Ltd.
April 13, 2011
Genzyme Japan K.K.
April 22, 2011
Shionogi & Co., Ltd.
April 22, 2011
Maruishi Pharmaceutical
Co., Ltd.
April 22, 2011
Dainippon Sumitomo
Pharma Co., Ltd.
May 16, 2011
Teijin Pharma Limited
May 17, 2011
Sosei Co. Ltd.
May 24, 2011
Takeda Pharmaceutical
Company Limited
June 6, 2011
Daiichi Sankyo
Company, Limited
June 8, 2011
Abbott Japan Co., Ltd.
July 1, 2011
Chugai Pharmaceutical
Co., Ltd.
July 1, 2011
Pizer Japan Inc.
July 1, 2011
Chugai Pharmaceutical
Co., Ltd.
July 1, 2011
GlaxoSmithKline K.K.
July 1, 2011
Chugai Pharmaceutical
Co., Ltd.
July 1, 2011
An additional administration for “pediatrics”
An additional indication for “treatment of acute rejection after renal transplantation”
An additional dosage and administration for “maximum daily dose, 3 g”
An additional indication for “conduction anesthesia”
An additional indication for “treatment of patients with polyarticular-course juvenile idiopathic arthritis”
An additional indication for “treatment of patients with unresectable pancreatic cancer”
An additional indication for “improvement of viraemia in compensated cirrhosis type C in combination therapy with
ribavirin”
An additional indication for “suppression of recurrent/relapsed mood episodes in patients with bipolar disorder”
An additional indication for “improvement of viraemia in compensated cirrhosis type C in combination therapy with
peginterferon alfa-2a (genetical recombination)”
Pharmaceuticals and Medical Devices
Safety Information No. 281
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July 2011